Production and use of highly functional, highly branched or hyperbranched polylysines

ABSTRACT

The present invention relates to new high-functionality, highly branched or hyperbranched polylysines, to processes for preparing them, and to their use.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. application Ser.No. 12/093,773, filed on May 15, 2008, which is a 371 of PCT/EP06/68479,filed on Nov. 15, 2006, and claims priority to the followingapplication: German Patent Application No. 102005056592.1, filed on Nov.25, 2005.

DESCRIPTION

The present invention relates to new high-functionality, highly branchedor hyperbranched polylysines, to processes for preparing them, and totheir use.

Both in research and in industry there is increasing interest indendrimeric and hyperbranched polypeptides. Potential biomedicalapplications exist for example in the development of new multipleantigen peptides (MAPs), as a carrier platform of contrast agents formagnetic resonance imaging or as gene transporters.

-   -   Dendritic polymers with a perfectly symmetrical structure,        referred to as dendrimers, can be prepared, starting from a        central molecule, by controlled, stepwise linkage of two or more        difunctional or polyfunctional monomers in each case with each        monomer already attached. With each linkage step in this        procedure there is an increase in the number of monomer end        groups (and hence of linkages), and polymers are obtained which        have treelike structures, ideally spherical, whose branches each        comprise exactly the same number of monomer units. This perfect        structure confers advantageous properties on the polymer, with        observations including, for example, a surprisingly low        viscosity and a high reactivity owing to the large number of        functional groups on the surface of the sphere. Preparation is        complicated, however, by the fact that each linkage step        requires the introduction and removal of protective groups, and        purifying operations, and for these reasons dendrimers are        typically prepared only on the laboratory scale.

Dendritic polymers with a less perfect structure, referred to ashyperbranched polymers, can be prepared in contrast by industrialprocesses. Besides perfect dendrimeric structures, hyperbranchedpolymers also contain linear polymer chains and unequal polymerbranches, although this does not substantially impair the polymerproperties as compared with those of the perfect dendrimers.

Hyperbranched polymers can be prepared by what is called the AB2 route.An AB2 molecule is a term used to refer to a trifunctional monomercontaining one reactive group A and two reactive groups B. Where thesegroups A and B are reactive with one another, hyperbranched polymers canbe produced by intermolecular reaction.

Regarding the definition of dendrimeric and hyperbranched polymers seealso P. J. Flory, J. Am. Chem. Soc. 1952, 74, 2718 and H. Frey et al.,Chemistry—A European Journal, 2000, 6, No. 14, 2499.

By “hyperbranched” is meant in the context of the present invention thatthe degree of branching (DB) is 10% to 99.9%, preferably 20% to 99%,more preferably 20%-95%.

By “dendrimeric” is meant in the context of the present invention thatthe degree of branching is 99.9%-100%.

The degree of branching is defined as follows:

DB [%]=100*(T+Z)/(T+Z+L)

where T denotes the average number of terminal monomer units, Z theaverage number of branched monomer units, and L the average number oflinear monomer units. With regard to the definition of the degree ofbranching see also H. Frey et al., Acta Polym. 1997, 48, 30.

By hyperbranched polypeptides are meant, in the context of thisinvention, non-crosslinked macromolecules synthesized from amino acids,which possess not only structural but also molecular nonuniformity. Onthe one hand they can be synthesized, starting from a central molecule,in analogy to dendrimers, but with a nonuniform chain length in thebranches. On the other hand they can also be synthesized linearly, withfunctional side groups, or else, as a combination with the two extremes,can have linear and branched moieties.

For the synthesis of hyperbranched polylysines there are three processesknown in principle:

-   Process 1 is based on the ring-opening addition polymerization of    ε-protected L-lysine-N-carboxyanhydrides (NCAs) with a nucleophilic    starter;-   Process 2 uses derivatives of L-lysine*2HCl that are activated on    the carboxyl group;-   Process 3 involves the direct thermal addition polymerization of    L-lysines.

Process 1, hyperbranched L-lysine polymers based on the ring-openingaddition polymerization of ε-protected L-lysine-N-carboxyanhydrides:

Hyperbranched poly(L-lysines) have been described by Klok et al. (WO2003/064452 and Macromolecules 2002, 35, 8718-8723). OrthogonallyN^(ε)-protected butoxycarbonyl-L-lysine (Boc-lysine;=temporaryprotective group) and ε-benzyloxycarbonyl-L-lysine (Z-lysine;=permanentprotective group) NCAs were subjected to ring-opening polymerizationusing an aliphatic amine (e.g., hexylamine) as starter. The temporaryprotective group was removed using trifluoroacetic acid (TFA), and thefree amino groups were employed as further starters for a newpolymerization. In the last step the Z protective groups were eliminatedusing hydrogen bromide/acetic acid (HBr/AcOH).

Additionally, hyperbranched poly(L-lysines) have been described byRodriguez-Hernández et al. (Biomacromolecules 2003, 4, 249-258). Amixture of N^(ε)-trifluoroacetyl-L-lysine-NCA (TFA-Lys-NCA) andZ-lysine-NCA were subjected to ring-opening polymerization with analiphatic amine. In a separate coupling stepN^(α),N^(ε)-di(9-fluorenyl-methoxycarbonyl)-L-lysine (N^(α),N^(ε)-diFmocLys) was introduced as a branching point. Deprotection with piperidinein DMF gave two new amine groups, which allow ring-openingpolymerization of TFA-Lys-NCA and Z-Lys-NCA. These reaction cycles wererepeated a number of times. Structurally similar hyperbranched blockcopolymers have also been described by Birchall et al. (Chem. Commun.1998, 1335-1336). α-Amino acid NCAs were subjected to ring-openingpolymerization with an aliphatic amine.N,N′-Di(benzyloxycarbonyl)-L-lysine p-nitrophenyl ester was introducedas a branching point, and after deprotection of H₂/Pd/C had two freeamine groups for the further ring opening of amino acid NCAs. Thesereaction cycles were repeated a number of times.

A disadvantage of all of these reaction regimes is that protectivegroups are required, which makes the reaction substantially moredifficult.

Process 2, hyperbranched L-lysine polymers based on derivatives ofL-lysine*2HCl which are activated on the carboxyl group.

Hyperbranched polylysines were prepared in a one-pot synthesis withactivation of the carboxyl group by means of N-hydroxysuccinimide (NHS).NHS-activated L-lysine*2HCl was stirred for 23 hours in dimethylsulfoxide (DMSO) with the addition of catalytic amounts ofdimethylaminopyridine (DMAP) and 3 equivalents of diisopropyl-ethylamine(DIEA), and the polymer was precipitated from ethyl acetate. The polymerhad a molecular weight of Mw=5100. Using the same reagents in a “pseudostepwise” polymerization, with repeated addition of monomer, molecularweights of Mw=8640 were attained. Additionally, the monomer was alsopolymerized onto tris(2-aminoethyl)-amines as a core molecule. In thisregard see also T. L. Menz and T. Chapman, Polym. Prep. 2003, 44(2), 842-743.

A disadvantage of the reaction regime disclosed by Menz is that thecarboxyl function has to be activated by a specialty reagent, socomplicating the reaction regime.

Process 3, thermal addition copolymerizations of amino acid mixtures:

The thermal addition polymerization of free lysine is known and has beencarried out under various reaction conditions.

Plaquet and coworkers (Biochimie 1975, 57 1395-1396) polymerizedL-lysine in aqueous solution at 105° C. for a period of up to 10 weeks,or else by heating at 165° C. for 8 hours. The reaction was carried outwithout catalyst and the yields, at below 72.5% without exception, werevery low.

Harada (Bull. Chem. Soc. Japan 1959, 32, 1007-1008) polymerized L-lysineat 180 to 230° C. for between 30 minutes and 2 hours under a nitrogenatmosphere. In a reaction below 180° C. only the formation of lactams isreported. Nothing is reported concerning molecular weight of astructure. The homopolymers obtained have a marked gel fraction. Thehomopolymerization of lysine hydrochloride was not achieved (p. 1008,bottom of left-hand column).

Rohlfing and coworkers (Archives of Biochemistry and Biophysics 1969,130, 441-448) polymerized L-lysine (free base) under a nitrogenatmosphere at between 186 and 192° C. They attained molecular weights ofup to 3600 Da and higher. Branched fractions as well were hypothesizedhere (see comparative experiment 11). The molecular weights>100 000described by Rohlfing et al. were not found in the comparativeexperiment.

WO 00/71600 describes the condensation of L-lysine monohydrate in apressure apparatus. The molecular weights of the homopolymers obtainedare low. Condensation of the free lysine base leads to crosslinkedcondensation products and is carried out either without catalysis or bycatalysis with mineral acids or salts thereof. Hydrochlorides must beconverted pre-reaction into the free base, using one equivalent of base,before they can be reacted in accordance with WO 00/71600.

Fox et al. (BioSystems 1976, 8, 40-44) used not only L-lysine but alsoL-lysine*HCl as starting monomers for the thermal polymerization at 195°C. In this case, when using L-lysine at a reaction temperature of 170°C., the cyclic lactam was obtained. L-Lysine*HCl was brought to reactiononly with the addition of orthophosphoric acid at 195° C. The molecularweights obtained here were low (see comparative experiment 12).

It was an object of the present invention to provide a simple processfor preparing polylysines that does not require protective-groupoperations or activation of carboxyl groups and in which it is alsopossible to attain higher molecular weights than those known from theprior art.

The object has been achieved by means of a process for preparingnoncrosslinked hyperbranched polylysines by reacting

-   -   (A) a salt of lysine with at least one acid,    -   (B) if appropriate, at least one amino acid other than lysine,    -   (C) if appropriate, at least one dicarboxylic or polycarboxylic        acid or copolymerizable derivatives thereof and    -   (D) if appropriate, at least one diamine or polyamine or        copolymerizable derivatives thereof,    -   (E) if appropriate, in at least one solvent at a temperature        from 120 to 200° C.    -   in the presence of at least one catalyst (F) selected from the        group consisting of        -   (F1) tertiary amines and amidines,        -   (F2) basic alkali metal salts, alkaline earth metal salts or            quaternary ammonium salts, and        -   (F3) alkoxides, alkanoates, chelates or organometallic            compounds of metals from groups IIIA to VIIIA or IB to VB in            the Periodic Table of the Elements.

With the process of the invention it is possible to preparenoncrosslinked hyper-branched polylysines having a weight-averagemolecular weight M_(w) of up to 750 000 Da, preferably up to 700 000 Da,more preferably up to 650 000 Da, very preferably up to 600 000 Da, andin, particular up to 550 000 Da.

Through the reaction regime of the invention it is also possible for thefirst time to prepare noncrosslinked hyperbranched polylysines having aweight-average molecular weight M_(w) of more than 5000 Da, preferablymore than 7500 Da, more preferably more than 10 000 Da, very preferablymore than 12 000 Da, in particular more than 15 000 Da, especially morethan 20 000 Da, and even more than 25 000 Da, and these polylysines arelikewise provided by the present invention.

Such polylysines of the invention, synthesized exclusively fromcomponent (A) with component (B), if appropriate, are notable for awater-solubility at 50° C. of more than 90% by weight for a molar weightof 5000 Da, preferably more than 6000 Da, and more preferably more than7000 Da.

The glass transition temperature T_(g), determined in accordance withASTM specification D3418-03 via differential scanning calorimetry,amounts in general to from −20 to 100° C., preferably from −10 to 80°C., and more preferably from 0 to 60° C.

The term “noncrosslinked” means, in accordance with the invention, thatthe polylysines obtained inventively from a salt (A) of lysine with atleast one acid exhibit a lower degree of crosslinking than polylysinesof the same weight-average molecular weight M_(w) that have beenobtained by polymerization of free lysine base.

One measure for this is, for example, a comparison of the gel content ofthe polylysines, i.e., the polylysine fraction which is insoluble whenstored at room temperature (23° C.) under water for 24 hours, divided bythe total amount of the sample, and multiplied by 100.

For polylysines of the invention the gel content is generally not morethan 20% as compared with polylysines obtained by polymerizing freelysine base, preferably not more than 10%, and more preferably not morethan 5%.

Modified polylysines, furthermore, are provided by the presentinvention.

The reaction of the invention is carried out in general at a temperaturefrom 120 to 200° C., preferably 130 to 180° C., and more preferably 150to 170° C., and very preferably 150 to 160° C.

The pressure at which the reaction is carried out plays a minor part. Ifa solvent (E) is used that has a lower boiling point than the desiredreaction temperature then it is sensible to apply pressure in order thatthe desired reaction temperature can be attained.

The reaction time varies according to the desired molecular weight andamounts in general to at least one hour, preferably at least 2 hours,more preferably at least 4 hours, very preferably at least 6 hours, andin particular at least 8 hours. In general the reaction is over afternot more than 72 hours, preferably after not more than 60 hours, morepreferably after not more than 48 hours, and very preferably after notmore than 36 hours.

The higher the desired molecular weight of the polylysines the longer,in general, the reaction time that must be chosen.

The reaction can be carried out continuously or, preferably, batchwise.The lysine reactant can be either included in its entirety in theinitial charge or else added, slowly, continuously to the reactor. Thelatter mode is also referred to as slow monomer addition. The reactionis preferably carried out in what is called a one-pot mode, in which themonomer is included in its entirety in the initial charge and thereaction is carried out in a reactor with backmixing. Also conceivable,however, are reaction regimes in a multistage reactor system, astirred-tank cascade for example, or in a tube reactor. In one preferredalternative embodiment of the present invention the reaction can becarried out in a compounder, extruder, intensive mixer or paddle dryer.

The reaction may, if appropriate, also be carried out with theassistance of ultrasound or of microwave radiation.

The individual components can be introduced at the beginning of thereaction regime or added in staggered form, depending on the stage ofpolymer formation at which it is desired to incorporate the respectivereaction components into the polymer.

In accordance with the invention lysine is used in the form of a salt(A) of the free lysine base with an acid, preferably an acid having apK_(a) of less than 2.2, more preferably a strong acid.

Examples of acids are acetic acid, formic acid, carbonic acid, glycolicacid, propionic acid or lactic acid.

Examples of acids having pK_(a) of less than 2.2 include for examplephosphoric acid (H₃PO₄), phosphorous acid (H₃PO₃), pyrophosphoric acid(H₄P₂O₇) or hydrogen sulfate (HSO₄ ⁻ ).

Examples of strong acids are sulfuric acid (H₂SO₄), perchloric acid,hydrochloric acid, and hydrobromic acid.

Very particular preference is given to sulfuric acid and hydrochloricacid, especially hydrochloric acid.

The formation of an inner salt for lysine is not included here as saltformation; the acid must be an acid other than lysine.

A further possibility is to use the salt of lysine in the form of anydesired hydrate. It is irrelevant for the purposes of the inventionwhich hydrate is employed.

Since lysine has two amino groups it is possible to employ, based on theamount of lysine, preferably more than 50 mol %, more preferably 50 to200 mol %, very preferably 75 to 200 mol %, and in particular 100 to 200mol % of acid for salt formation.

If appropriate, albeit it less preferably, the carboxy group of thelysine can also be present in the form of an ester, for example, aC₁-C₁₀ alkyl ester, preferably a C₁-C₄ alkyl ester.

Lysine can be used in enantiomerically pure form or as a racemate,preferably as a racemate or in the form of L-lysine, more preferably inthe form of L-lysine.

It will be appreciated that L-lysine can be also be copolymerized withother amino acids (B). Mention may be made here, for example, ofglycine, alanine, β-alanine, valine, leucine, isoleucine, tert-leucine,phenylalanine, tyrosine, tryptophan, proline, aspartic acid, glutamicacid, asparagine, glutamine, serine, threonine, cysteine, methionine,arginine, histidine, 4-aminobutyric acid, cystine, citrulline, theanine,homocysteine, 4-hydroxyproline, alliin or ornithine.

Amino acids (B) in this context are amino acids which have at least oneprimary or secondary amino group and at least one carboxyl group.

Additionally it is possible as well for the noncrosslinked hyperbranchedpolylysines to be randomly or block-copolymerized with carboxylic acids(C) or amines (D), in which case it should be ensured that the overallmolar ratio of amino groups to carboxyl groups in the reaction mixtureis between 3:1 to 1:3, preferably 3:1 to 1:2, more preferably 3:1 to1:1, and very preferably 2.5:1 to 1.5:1.

Dicarboxylic and polycarboxylic acids (C) suitable for thiscopolymerization typically have at least 2, preferably 2 to 4, morepreferably 2 to 3, and very preferably 2 carboxyl groups. Preferreddicarboxylic and polycarboxylic acids (C) comprise 2 to 30 carbon atomatoms and can be aliphatic, cycloaliphatic or aromatic.

Examples of suitable dicarboxylic acids include the following: oxalicacid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelicacid, suberic acid, azelaic acid, sebacic acid,undecane-α,ω-dicarboxylic acid, dodecane-α,ω-dicarboxylic acid, cis- andtrans-cyclohexane-1,2-dicarboxylic acid, cis- andtrans-cyclohexane-1,3-dicarboxylic acid, cis- andtrans-cyclohexane-1,4-dicarboxylic acid, cis- andtrans-cyclopentane-1,2-dicarboxylic acid, and cis- andtrans-cyclopentane-1,3-dicarboxylic acid, it being possible for thedicarboxylic acids to be substituted by one or more radicals selectedfrom:

C₁-C₁₀ alkyl groups, examples being methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,sec-pentyl, neopentyl, 1,2-dimethylpropyl, isoamyl, n-hexyl, isohexyl,sec-hexyl, n-heptyl, isoheptyl, n-octyl, 2-ethylhexyl, n-nonyl orn-decyl,C₃-C₁₂ cycloalkyl groups, examples being cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl and cyclododecyl; preference is given tocyclopentyl, cyclohexyl and cycloheptyl,alkylene groups such as methylene or ethylidene, and/orC₆-C₁₄ aryl groups such as, for example, phenyl, 1-naphthyl, 2-naphthyl,1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl,3-phenanthryl, 4-phenanthryl, and 9-phenanthryl, preferably phenyl,1-naphthyl, and 2-naphthyl, more preferably phenyl.

Examples that may be mentioned of substituted dicarboxylic acids includethe following: 2-methylmalonic acid, 2-ethylmalonic acid,2-phenylmalonic acid, 2-methylsuccinic acid, 2-ethylsuccinic acid,2-phenylsuccinic acid, itaconic acid, and 3,3-dimethylglutaric acid.

Also suitable are aromatic dicarboxylic acids such as, for examplephthalic acid, isophthalic acid or terephthalic acid.

Examples of suitable tricarboxylic and tetracarboxylic acids includetrimesic acid, trimellitic acid, pyromellitic acid, butanetricarboxylicacid, naphthalenetricarboxylic acid, and cyclohexane-1,3,5-tricarboxylicacid.

Excluded from consideration as component (C) are those dicarboxylic orpolycarboxylic acids which have activated double bonds, such asα,β-ethylenically unsaturated double bonds, for example, and/or aminoacids (B).

Preferred components (C) are those dicarboxylic or polycarboxylic acidswhich apart from carboxyl groups contain no further functional groups.

It is additionally possible to use mixtures of two or more of theaforementioned carboxylic acids. The carboxylic acids can be used eitheras such or in the form of derivatives. Such derivatives are, inparticular,

-   -   the anhydrides of the aforementioned carboxylic acids, in either        monomeric or polymeric form;    -   the esters of the aforementioned carboxylic acids, such as        -   monoalkyl or dialkyl esters, preferably C1 to Ca-alkyl            esters, more preferably monomethyl or dimethyl esters or the            corresponding monoethyl or diethyl esters, but also the            monoalkyl and dialkyl esters derived from higher alcohols            such as, for example n-propanol, isopropanol, n-butanol,            isobutanol, tert-butanol, n-pentanol, and n-hexanol,        -   monovinyl and divinyl esters, and        -   mixed esters, preferably methyl ethyl esters.

It is also possible to use a mixture of a carboxylic acid and one ormore of its derivatives, or a mixture of two or more differentderivatives of one or more dicarboxylic acids.

Particular preference is given to using, as carboxylic acid, succinicacid, glutaric acid, adipic acid, phthalic acid, isophthalic acid,terephthalic acid or their monomethyl or dimethyl esters.

Suitable amines (D) have typically at least 2, preferably 2 to 6, morepreferably 2 to 4 amino groups, having generally 2 to 30 carbon atoms,and can be aliphatic, cycloaliphatic or aromatic. The amines (D) haveprimary and/or secondary amino groups.

Suitable diamines are preferably those of the formula R¹—NH—R²—NH—R³ inwhich R¹ and R³ independently of one another are hydrogen or an alkylradical, cycloalkyl radical, aryl radical or arylalkyl radical having 1to 20 carbon atoms. The alkylene radical R² may be linear or elsecyclic.

Examples of preferred diamines are ethylenediamine, thepropylenediamines (1,2-diaminopropane and 1,3-diaminopropane),N-methylethylenediamine, piperazine, tetramethylenediamine(1,4-diaminobutane), N,N′-dimethylethylenediamine,N-ethylethylenediamine, 1,5-diaminopentane,1,3-diamino-2,2-diethylpropane, 1,3-bis(methylamino)propane,hexamethylenediamine (1,6-diaminohexane), heptanediamine, octanediamine,nonanediamine, decanediamine, dodecanediamine, hexadecanediamine,tolylenediamine, xylylenediamine, diaminodiphenylmethane,diaminodicyclohexylmethane, phenylenediamine, cyclohexylenediamine,bis(aminomethyl)cyclohexane, diaminodiphenyl sulfone,1,5-diamino-2-methylpentane, 3-(propylamino)propylamine,N,N′-bis(3-aminopropyl)piperazine, N,N′-bis(3-amino-propyl)piperazine,isophoronediamine (IPDA), 3(or 4),8(or9)-bis(aminomethyl)-tricyclo[5.2.1.0^(2.6)]decane isomer mixtures,2-butyl-2-ethyl-1,5-pentamethylenediamine, 2,2,4- or2,4,4-trimethyl-1,6-hexamethylenediamine, 2-aminopropylcyclohexylamine,3(4)-aminomethyl-1-methylcyclohexylamine, 1,4-diamino-4-methylpentane,amine-terminated polyoxyalkylene polyols (so-called Jeffamines) oramine-terminated polytetramethylene glycols.

Preference is given to butylenediamine, pentanediamine,hexamethylenediamine, tolylenediamine, xylylenediamine,diaminodiphenylmethane, diaminodicyclohexylmethane, phenylenediamine,cyclohexylenediamine, diaminodiphenyl sulfone, isophoronediamine,bis(aminomethyl)cyclohexane, amine-terminated polyoxyalkylene polyols(so-called Jeffamines) or amine-terminated polytetramethylene glycols.

Examples of suitable amines having three or more reactive primary and/orsecondary amino groups are tris(aminoethyl)amine,tris(aminopropyl)amine, tris(aminohexyl)amine, trisaminohexane,4-aminomethyl-1,8-octanediamine, trisaminononane, bis(aminoethyl)amine,bis(aminopropyl)amine, bis(aminobutyl)amine, bis(aminopentyl)amine,bis(aminohexyl)amine, N-(2-aminoethyl)propanediamine, melamine,oligomeric diaminodiphenylmethanes (polymer-MDA),N,N′-bis(3-aminopropyl)ethylenediamine,N,N′-bis(3-aminopropyl)butanediamine,N,N,N′,N′-tetra(3-aminopropyl)ethylenediamine,N,N,N′,N′-tetra(3-aminopropyl)butylenediamine, amine-terminatedpolyoxyalkylene polyols having a functionality of three or more(so-called Jeffamines), polyethyleneimines having a functionality ofthree or more, or polypropyleneimines having a functionality of three ormore.

Preferred amines having three or more reactive primary and/or secondaryamino groups are tris(aminoethyl)amine, tris(aminopropyl)amine,tris(aminohexyl)amine, trisaminohexane, 4-aminomethyl-1,8-octanediamine,trisaminononane, bis(aminoethyl)amine, bis(aminopropyl)amine,bis(aminobutyl)amine, bis(aminopentyl)amine, bis(aminohexyl)amine,N-(2-aminoethyl)propanediamine, melamine or amine-terminatedpolyoxyalkylene polyols having a functionality of three or more(so-called Jeffamines).

Particular preference is given to amines having three or more primaryamino groups, such as tris(aminoethyl)amine, tris(aminopropyl)amine,tris(aminohexyl)amine, trisaminohexane, 4-aminomethyl-1,8-octanediamine,trisaminononane or amine-terminated polyoxyalkylene polyols having afunctionality of three or more (so-called Jeffamines).

It is also possible to use mixtures of two or more carboxylic acidsand/or carboxylic acid derivatives, or mixtures of two or more amines.The functionality of the various carboxylic acids or amines may be thesame or different.

The reaction of the lysine (A) and, if appropriate, of the additionalmonomers (B) to (D) can optionally take place in a solvent (E). In thiscontext it is possible in general to use all solvents, preferably thosewhich are inert toward the respective reactants under the reactionconditions. It is preferred to operate in organic solvents, such asdecane, dodecane, benzene, toluene, chlorobenzene, dichlorobenzene,xylene, dimethylformamide, dimethylacetamide or solvent naphtha. Alsoconceivable and additionally preferred, however, are water and alkanolshaving 1 to 10 carbon atoms, especially methanol, ethanol, isopropanol,n-butanol, and 2-ethylhexanol.

In one preferred embodiment of the process of the invention the reactionis carried out in bulk, in other words without solvent.

It is also possible, however, for minor amounts of water to be present:for example, up to 20% by weight, preferably up to 15%, more preferablyup to 10%, and very preferably up to 5% by weight, with respect to thesalt of lysine.

The water liberated during the reaction can be separated off bydistillation, if appropriate with passage over the liquid phase of a gaswhich is inert under the reaction conditions, with passage through theliquid phase of a gas which is inert under the reaction conditions, ifappropriate under reduced pressure, and in this way said water can beremoved from the reaction equilibrium. This also has the effect ofaccelerating the reaction.

Gases inert under the reaction conditions may be, for example, noblegases, such as helium or argon, for example, nitrogen, carbon monoxideor carbon dioxide.

The reaction is accelerated by adding catalysts (F) or catalystmixtures.

Suitable catalysts are compounds which catalyze esterification oramidation and are selected from the group of

-   -   (F1) tertiary amines and amidines,    -   (F2) basic alkali metal salts, alkaline earth metal salts or        quaternary ammonium salts, and    -   (F3) alkoxides, alkanoates, chelates or organometallic compounds        of metals from groups IIIA to VIIIA or IB to VB in the Periodic        Table of the Elements.

Tertiary amines and amidines (F1) are those which have no free hydrogenatoms on the amino groups but whose nitrogen atoms are instead connectedvia three bonds exclusively to carbon atoms. Preferred tertiary aminesand amidines are those having a pK_(b) of more than 8.9, more preferablymore than 10.3. With very particular preference the tertiary amines andamidines have only low volatility at the reaction temperature, and inparticular have a boiling point above the reaction temperature.

Examples of tertiary amines are trioctylamine, tridodecylamine.tribenzylamine, N,N,N′,N′-tetramethylethylenediamine, 1-methylpyrrole,pyridine, 4-dimethylaminopyridine, picoline, N,N′-dimethylpiperazine,N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine,N,N-dimethylaniline, N,N-dimethylbenzylamine,1,4-diazabicyclo-[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene or1,8-diazabicyclo[5.4.0]undec-7-ene. Examples of amidines are imidazoles,such as N-methylimidazole, imidazole, 1-methylimidazole,2-methylimidazole or 1,2-dimethylimidazole.

The basic alkali metal, alkaline earth metal or quaternary ammoniumsalts (F2) are hydroxides, oxides, carbonates, hydrogen carbonates,C₁-C₁₀ alkoxides or C₁-C₁₀ alkanoates with cations from the series ofthe alkali metals or alkaline earth metals or quaternary ammonium ions.

Alkali metals are preferably Li, Na, K or Cs, more preferably Na and K.Alkaline earth metals are preferably Mg and Ca. Quaternary ammonium ionscan have 4 to 32 carbon atoms and be substituted by alkyl, cycloalkyl,aryl or arylalkyl, preferably by alkyl or arylalkyl, and more preferablyby alkyl.

Preferred C₁-C₁₀ alkoxides are C₁-C₄ alkoxides, more preferablymethoxide, ethoxide, isopropoxide, and n-butoxide, very preferablymethoxide and ethoxide, and especially methoxide.

Preferred C₁-C₁₀ alkanoates are C₁-C₄ alkanoates, particular preferencebeing given to acetate.

Preferred compounds (F2) are lithium, sodium, potassium or cesiumhydroxide, lithium, sodium, potassium or cesium carbonate, lithium,sodium, potassium or cesium acetate, particular preference being givento sodium or potassium hydroxide.

Compounds (F3) are alkoxides, alkanoates, chelates or organometalliccompounds of metals from groups IIIA to VIIIA or IB to VB in thePeriodic Table of the Elements.

Examples of alkoxides are C₁-C₂₀ alkoxides, preferably C₁-C₄ alkoxides,more preferably methoxide, ethoxide, isopropoxide, and n-butoxide, verypreferably methoxide and ethoxide, and especially methoxide.

Examples of alkanoates are C₁-C₂₀ alkanoates, preferably C₁-C₄alkanoates, particular preference being given to acetate.

Chelates are cyclic compounds in which metals and moieties with loneelectron pairs form a ring. A preferred chelate former isacetylacetonate.

Organometallic compounds are those having a direct metal-carbon bond.

Preferred metals are boron, aluminum, tin, zinc, titanium, antimony,zirconium or bismuth.

Preferred compounds (F3) are titanium tetrabutoxide, titaniumtetraisopropoxide, zirconium acetylacetonate, zirconium tetrabutoxide,tin(II) n-octanoate, tin(II) 2-ethylhexanoate, tin(II) laurate,dibutyltin oxide, dibutyltin dichloride, dibutyltin diacetate,dibutyltin dilaurate, dibutyltin dimaleate, dioctyltin diacetate,antimony triethoxide or boronic acid derivatives—for example,pyridineboronic acid.

Preferred catalysts are (F1) and (F2), particular preference being givento compounds (F2).

The compounds (A) to (E) are reacted with one another, for the reactionof the invention, in the following proportions:

-   (B) up to 100 mol % based on (A), preferably 0 to 75 mol %, more    preferably 0-50 mol %, very preferably 0-25 mol %, in particular    0-15 mol %, and especially 0 mol %,-   (C) 0 to 50 mol % based on (A), preferably 0 to 30 mol %, more    preferably 0-25 mol %, very preferably 0-10 mol %, in particular 0-5    mol %, and especially 0 mol %.-   (D) 0 to 50 mol % based on (A), preferably 0 to 30 mol %, more    preferably 0-25 mol %, very preferably 0-10 mol %, in particular 0-5    mol %, and especially 0 mol %,-   (E) 0-200% by weight with respect to the sum of components (A) to    (D), preferably 0-100%, more preferably 0-75%, very preferably    0-50%, in particular 0 - 25%, and especially 0% by weight, and-   (F1) or-   (F2) up to 110 mol %, preferably up to 105 mol %, more preferably up    to 100 mol %, and generally at least 80 mol % with respect to the    acid which forms the salt with lysine, and/or-   (F3) 0.1 to 20 mol % with respect to the sum of components (A) to    (D), and preferably 0.1 to 15 mol %.

After the reaction, in other words without additional modification, thehigh-functionality highly branched polypeptides prepared by the processof the invention are terminated by amino and/or carboxyl groups. Theydissolve readily in polar solvents, for example in water, alcohols, suchas methanol, and in modified form also in ethanol, butanol,alcohol/water mixtures, dimethylformamide, dimethylacetamide,N-methylpyrrolidone, chloroform, ethylene carbonate or propylenecarbonate.

A high-functionality polypeptide for the purposes of the invention is aproduct which has at least three, preferably at least six, and inparticular at least ten functional groups. In principle there is noupper limit on the number of functional groups, although products havinga very large number of functional groups may exhibit unwantedproperties, such as high viscosity or a poor solubility. Thehigh-functionality polypeptides of the present invention generallycontain not more than 200 functional groups, preferably not more than100 functional groups. By functional groups here are meant primary,secondary or tertiary amino groups or carboxyl groups. In addition thehigh-functionality highly branched polypeptide may have furtherfunctional groups which do not participate in the synthesis of thehighly branched polymer (see below). These further functional groups maybe introduced by means of diamines or polyamines, or dicarboxylic orpolycarboxylic acids, which in addition to primary and secondary aminogroups, or acid groups, also contain further functional groups.

In one further preferred embodiment the polypeptides of the inventionmay comprise further functional groups. The functionalization in thiscase can take place during the reaction, i.e., during thepolycondensation reaction that brings about the increase in molecularweight, or else after the end of the polycondensation reaction, bysubsequent functionalization of the resulting polypeptides.

If, before or during the molecular weight increase, components are addedwhich in addition to amino and/or carboxyl groups have furtherfunctional groups, then a polypeptide is obtained which has, randomlydistributed, further functional groups—that is, functional groups otherthan the amino or carboxyl groups.

By way of example, before or during the polycondensation, it is possibleto add components (G), which have either primary or secondary aminogroups or carboxyl groups, hydroxyl groups, mercapto groups, tertiaryamino groups, ether groups, urea groups, sulfonic acid groups,phosphonic acid groups, silane groups, siloxane groups, aryl radicals orshort-chain or long-chain, linear or branched alkyl radicals which ifappropriate are also partly fluorinated or perfluorinated.

Hydroxyl-containing components (G) which can be added forfunctionalization comprise, for example, ethanolamine,N-methylethanolamine, propanolamine, isopropanolamine, butanolamine,2-amino-1-butanol, 2-(butylamino)ethanol, 2-(cyclohexylamino)ethanol,2-(2′-aminoethoxy)ethanol or higher alkoxylation products of ammonia, or4-hydroxypiperidine, 1-hydroxyethylpiperazine, diethanolamine,dipropanolamine, diisopropanolamine, tris(hydroxymethyl)aminomethane ortris(hydroxyethyl)aminomethane, and also dimethylolpropionic acid,dimethylolbutyric acid, hydroxypivalic acid, lactic acid or glycolicacid.

Mercapto-comprising components which can be added for functionalizationcomprise, for example, cysteamine, mercaptoacetic acid ormercaptoethanol. With tertiary amino groups the highly branchedpolypeptides can be functionalized by, for example, concomitant use ofdi(aminoethyl)methylamine, di(aminopropyl)methylamine orN,N-dimethylethylenediamine. With ether groups the highly branchedpolypeptides can be functionalized by concomitant use ofamine-terminated polyetherols (so-called Jeffamines) or withpolyether-carboxylic acids. With sulfonic or phosphonic acid groups thehighly branched polypeptides can be functionalized by, for example,concomitant use of aminosulfonic acids or aminophosphonic acids. Withgroups comprising silicon the highly branched polypeptides can befunctionalized by concomitant use of hexamethyldisilazane,N-(3-trimethylsilylethyl)ethylenediamine,3-aminopropyltrimethylsiloxane, 3-aminopropyltriethylsiloxane,3-isocyanatopropyltrimethylsiloxane or3-isocyanatopropyltriethylsiloxane. With long-chain alkyl radicals thehighly branched polypeptides can be functionalized by concomitant use ofalkylamines, alkylcarboxylic acids, alkylsulfonic acids or alkylisocyanates.

The polypeptides can also be functionalized, additionally, through theuse of small amounts of monomers (H) which do not have amino groups anddo not have carboxyl groups but instead have functional groups which aredifferent from amino groups or carboxyl groups but are able to reactwith amino or carboxyl groups. Mention may be made here, by way ofexample, of alcohols having a functionality of two, three or more, whichcan be incorporated into the polypeptide via ester functions. Thus, forexample, hydrophobic properties can be achieved through the addition oflong-chain alkanediols, while polyethylene oxide diols or triols producehydrophilic properties in the polypeptide.

The stated functional groups other than amine or carboxylic acid groupsthat are introduced before or during the polycondensation are introducedgenerally in amounts of 0.1 to 80 mol %, preferably in amounts of 1 to50 mol %, based on the sum of the amino groups and carboxylic acidgroups.

The present invention further provides modified polylysines in which theaccessible amino and/or carboxyl groups have been at least partlyfurther modified, i.e., reacted with reagents which alter the propertiesof the polylysine thus modified. Examples of these properties includesolubility, dispersibility, hydrophilicity, hydrophobicity, andrheology.

The polylysines are modified preferably with the polylysines of theinvention, as described above, whose preparation is based on thereaction of a salt of lysine with an acid. Also conceivable, however, isthe modification of polylysines obtained in any desired way, having beenprepared, for example, by polymerization or copolymerization oflysine-containing reactants other than (A)—free lysine base, forexample.

The polylysines which can be employed for such modification ought tohave a weight-average molecular weight M_(w) or more than 1000 Da,preferably more than 1500 Da, more preferably more than 2000 Da, verypreferably more than 2500 Da, in particular 3000 Da, and especially 5000Da. With advantage it is also possible to use polylysines which have anM_(w) or more than 7500 Da, more than 10 000 Da, more than 15 000 Da, oreven more than 20 000 Da.

An upper limit on the weight-average molecular weight M_(w) is notessential to the invention. It is possible to use, for example,polylysines having an M_(w) up to 750 000 Da, preferably up to 600 000Da, more preferably up to 500 000 Da, very preferably up to 400 000 Da,and in particular up to 300 000 Da.

The polylysines which can be employed may for example comprise primary,secondary or tertiary, free or protonated amino groups, calculated asNH₂, in an amount of 1% to 21.9% by weight, preferably 3% to 18% byweight.

The polylysines which can be employed may for example have a free ordeprotonated acid group content, calculated as COOH, of 0 to 30% byweight and preferably 0 to 15% by weight.

Subsequent functionalization of high-functionality highly branchedpolypeptides comprising amino groups can be achieved for example byaddition of molecules without amino groups or carboxyl groups (I) butcomprising acid groups, isocyanate groups, keto groups or aldehydegroups, or activated double bonds, examples being molecules comprisingacrylic double bonds. By way of example it is possible to obtainpolypeptides comprising acid groups by reaction with acrylic acid ormaleic acid and derivatives thereof, esters for example, with subsequenthydrolysis, if appropriate.

Additionally it is possible to convert high-functionality polypeptidescomprising amino groups into high-functionality polypeptide polyols byreaction with alkylene oxides (J1), such as ethylene oxide, propyleneoxide or butylene oxide, for example.

A further possibility for the functionalization of the amino groups inthe high-functionality polypeptides lies in the at least partialreaction of the amino groups with lactones and/or lactams, to formpolyester chains with a terminal hydroxyl group which start out fromthese amino groups. Exemplary lactams are ε-caprolactam, δ-valerolactam,γ-butyrolactam, N-methylcaprolactam, and N-methylpyrrolidone. Exemplarylactones are ε-caprolactone, δ-valerolactone, and γ-butyrolactone.

A further possibility of preparing polypeptide/polyether compounds liesin the reaction of the polypeptides with polyalkylene oxides (J2) whichare terminated by amino groups or acid groups and have a functionalityof one, two or more, preferably polyethylene oxides, polypropyleneoxides or polyethylene-propylene oxides.

By salt formation with protic acids or by quaternization of the aminofunctions with alkylating reagents (K), such as methyl halides, alkyltosylates or dialkyl sulfates, the high-functionality, highly branchedpolypeptides can be made soluble in water or dispersible in water.

The salt formation can also be carried out by mixing or reacting theamino groups of the hyperbranched polymers of the inventionstoichiometrically or substoichiometrically with acidic components orsalts thereof that have long-chain linear or branched alkyl radicals,cycloalkyl radicals substituted if appropriate, or aryl radicalssubstituted if appropriate, and which are commonly known as soaps orsurfactants.

Acidic components of this kind may preferably contain at least one, withparticular preference precisely one, carboxyl, sulfonic acid, sulfate orphosphonic acid group.

The hyperbranched polymers may for example be reacted with alkyl- oralkenylcarboxylic acids, such as, for example, octanoic acid, nonanoicacid, decanoic acid, dodecanoic acid, hexadecanoic acid, stearic acid,oleic acid, linoleic acid, linolenic acid or their Li, Na, K, Cs, Ca orammonium salts, with alkylsulfonic acids, examples being octanesulfonicacid, dodecanesulfonic acid, stearylsulfonic acid or oleylsulfonic acid,or their Li, Na, K, Cs, Ca or ammonium salts, with camphorsulfonic acid,cyclododecylsulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,4-hexylbenzenesulfonate, 4-octylbenzenesulfonate,4-decylbenzenesulfonate or 4-dodecylbenzenesulfonate or their Li, Na, K,Cs, Ca or ammonium salts, or with alkyl sulfates, examples being n-alkylsulfates or secondary alkyl sulfates. This produces ionicpolylysine-surfactant complexes which, for example, haveliquid-crystalline properties or may act as polymeric ionic liquids.

The alkyl, cycloalkyl or aryl radicals may in this case have up to 20carbon atoms, preferably 6 to 20, more preferably 7 to 20.

In order to achieve water repellency (hydrophobicity) it is possible foramine-terminated, high-functionality, highly branched polypeptides to bereacted with saturated or unsaturated long-chain carboxylic acids (L),with amino-reactive derivatives thereof, or else with aliphatic oraromatic isocyanates, trialkylsilyl halides, partly or fully fluorinatedalcohols, alkyl halides, carboxylic acids or amines. Polypeptidesterminated by carboxylic acid groups can be hydrophobicized by reactionwith long-chain alkylamines or long-chain aliphatic monoalcohols.

In order to achieve nonionic hydrophilicization it is possible to reactamine-terminated, high-functionality, highly branched polypeptides withaliphatic or aromatic isocyanates that additionally comprisepolyethylene glycol chains.

Polypeptides terminated by carboxylic acid groups can be nonionicallyhydrophilicized by reaction with long-chain, preferably monofunctionalpolyethylene glycols or polyethylene glycol amines (Jeffamines).

In order to achieve an amphiphilic character the high-functionality,highly branched polypeptides can also be modified with hydrophobic andhydrophilic agents simultaneously—for example, with long-chain aliphaticcarboxylic acids, alcohols, amines or isocyanates which have afunctionality of one, two or more, and at the same time with alcohols,amines, acids or isocyanates which contain polyethylene glycol chainsand have a functionality of one, two or more.

For purification, specifically also for the separation of the inorganicsalts that form during the preparation, the polymers of the inventioncan be dissolved, for example, in polar or apolar solvents, the saltsnot going into solution and being separable from the polymer byfiltration. By way of example mention may be made here of thedissolution of the unmodified polylysine in ethanol, where the potassiumchloride formed in the reaction was precipitated as a sediment and couldbe separated from the polymer solution by filtration.

The present invention also provides for the use of thehigh-functionality highly branched polypeptides of the invention asadhesion promoters and thioxotropic agents, solubilizers, phase transferreagents for water-insoluble chemicals, phase transfer reagents forwater-soluble chemicals, surface modifiers, and components in theproduction of printing inks, paints, coatings, adhesives, sealants,corrosion control products, casting elastomers, and foams.

EXAMPLES Example 1 Condensation Product of L-lysine*1 HCl, Reaction at150° C. with NaOH Added, without Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and solid NaOH (2.4 g, 60 mmol) weretriturated in a mortar and the mixture was subsequently heated in aSchlenk tube at 150° C. During the reaction, samples were taken after14, 24, 38, and 48 hours, dissolved in water, the solution was filtered,and the molecular weights were determined by GPC analysis. The GPCanalysis took place on untreated samples, taken directly from thereaction mixture, by means of a column combination comprising OHpakSB-803 HQ and SB-804 HQ (Shodex) in aqueous solution with the additionof 0.1 mol/l sodium hydrogen carbonate at 30° C., with a flow rate of0.5 ml/min and with polyethylene oxide as standard. Detection took placeusing a UV detector which operated at a wavelength of 230 nm.

TABLE 1 Polycondensation of L-lysine*HCl at 150° C. with NaOH addedReaction time Molecular weight (Mw) Polydispersity 14 hours   2500 g/mol2.2 24 hours   3400 g/mol 2.4 38 hours 14 600 g/mol 5 48 hours 28 100g/mol 9.3

Example 2 Condensation Product of L-lysine*HCl, Reaction at 150° C. withKOH added, without Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and KOH (3.3 g, 60 mmol) were triturated ina mortar and the mixture was subsequently heated in a Schlenk tube at150° C. During the reaction, samples were taken after 14, 24, 38, and 48hours, dissolved in water, the solution was filtered, and the molecularweights were determined as described in Example 1 (see Table 2).

TABLE 2 Polycondensation of L-lysine*HCl at 150° C. with KOH addedReaction time Molecular weight (Mw) Polydispersity 14 hours   3300 g/mol2.8 24 hours   9900 g/mol 4.9 38 hours 36 100 g/mol 11.3 48 hours 283700 g/mol  61.8

Example 3 Condensation Product of L-lysine*HCl, Reaction at 150° C. withNaOH and Zirconium(IV) Butoxide added, without Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and NaOH (2.4 g, 60 mmol) were trituratedin a mortar and the mixture, following addition of 1 ml of zirconium(IV)butoxide (Zr(OBu)₄), was heated in a Schlenk tube at 150° C. During thereaction, samples were taken after 14, 24, 38, and 48 hours, dissolvedin water, the solution was filtered, and the molecular weights weredetermined by GPC as described in Example 1 (see Table 3).

TABLE 3 Polycondensation of L-lysine*HCl at 150° C. with NaOH andzirconium(IV) butoxide added Reaction time Molecular weight (Mw)Polydispersity 14 hours   3100 g/mol 2.0 24 hours   7700 g/mol 2.8 38hours 25 700 g/mol 5.5 48 hours 57 300 g/mol 10.4

Example 4 Condensation Product of L-lysine*HCl, Reaction at 150° C. withKOH and Zirconium(IV) Butoxide added, without Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and KOH (3.3 g, 60 mmol) were triturated ina mortar and the mixture, following addition of 1 ml of zirconium(IV)butoxide (Zr(OBu)₄), was heated in a Schlenk tube at 150° C. During thereaction, samples were taken after 14, 24, 38, and 48 hours, dissolvedin water, the solution was filtered, and the molecular weights weredetermined by GPC as described in Example 1 (see Table 4).

TABLE 4 Polycondensation of L-lysine*HCl at 150° C. with KOH andzirconium(IV) butoxide added Reaction time Molecular weight (Mw)Polydispersity 14 hours   4900 g/mol 2.5 24 hours  19 400 g/mol 4.6 38hours 139 000 g/mol 23 48 hours 510 000 g/mol 107

Example 5 Condensation Product of L-lysine*HCl, Reaction at 150° C. withNaOH and Dibutyltin Dilaurate added, without Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and NaOH (2.4 g, 60 mmol) were trituratedin a mortar and the mixture, following addition of 1 ml of dibutyltindilaurate, was heated in a Schlenk tube at 150° C. During the reaction,samples were taken after 14, 24, 38, and 48 hours, dissolved in water,the solution was filtered, and the molecular weights were determined byGPC as described in Example 1 (see Table 5).

TABLE 5 Polycondensation of L-lysine*HCl at 150° C. with NaOH anddibutyltin dilaurate added Reaction time Molecular weight (Mw)Polydispersity 14 hours   2300 g/mol 2.5 24 hours   5300 g/mol 4.1 38hours 37 000 g/mol 21.2 48 hours 49 400 g/mol 27.9

Example 6 Condensation Product of L-lysine*HCl, Reaction at 150° C. withNaOH and Triphenyl Phosphite added, without Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and NaOH (2.4 g, 60 mmol) were trituratedin a mortar and the mixture, following addition of 1 ml of triphenylphosphite, was heated in a Schlenk tube at 150° C. During the reaction,samples were taken after 14, 24, 38, and 48 hours, dissolved in water,the solution was filtered, and the molecular weights were determined byGPC as described in Example 1 (see Table 6).

TABLE 6 Polycondensation of L-lysine*HCl at 150° C. with NaOH andtriphenyl phosphite added Reaction time Molecular weight (Mw)Polydispersity 14 hours   3200 g/mol 3.2 24 hours   6400 g/mol 4.6 38hours 14 000 g/mol 8.7 48 hours 18 400 g/mol 12.7

Example 7 Condensation Product of L-lysine*HCl, Reaction at 180° C. withNaOH added, without Reduced Pressure

L-Lysine*HCl (5.5 g, 30 mmol) and NaOH (1.2 g, 30 mmol) were trituratedin a mortar and the mixture was subsequently heated in a Schlenk tube at180° C. After 24 hours the mixture was cooled to room temperature andthe viscous melt was dissolved in water and filtered. The molecularweight Mw of the polymer, determined by GPC in accordance with Example1, was 20 600 g/mol, the polydispersity 4.9.

Example 8 Condensation Product of L-lysine*HCl, Reaction at 150° C. withNaOH, with Reduced Pressure

L-Lysine*HCl (11 g, 60 mmol) and NaOH (2.4 g, 60 mmol) were trituratedin a mortar and the mixture was subsequently heated under reducedpressure in a Schlenk tube at 150° C. During the reaction, samples weretaken after 14, 24, 38, and 48 hours, dissolved in water, the solutionwas filtered, and the molecular weights were determined by GPC asdescribed in Example 1 (see Table 8).

TABLE 8 Polycondensation of L-lysine*HCl at 150° C. with NaOH added andwith reduced pressure Reaction time Molecular weight (Mw) Polydispersity14 hours   5800 g/mol 3.3 24 hours  29 300 g/mol 8.4 38 hours 122 800g/mol 24.7 48 hours 503 600 g/mol 133.1

Example 9 Condensation Product of L-lysine*HCl, Reaction at 150° C. withNaOH and Dibutyltin Dilaurate with Reduced Pressure

A 4-I four-necked flask equipped with stirrer, internal thermometer, gasinlet tube, and descending condenser with reduced-pressure connectionand receiver was charged with 1000 g of L-lysine hydrochloride, 218 g ofsolid sodium hydroxide, 100 g of water, and 0.3 g of dibutyltindilaurate and the mixture was heated with stirring at an internaltemperature of 150° C. After a reaction time of 5 hours, water wasdistilled off under reduced pressure (200 mbar), and after the majoramount of water had gone over the temperature was slowly raised to 180°C. and the pressure was reduced to 10 mbar. After 8 hours 240 g of waterdistillate had been collected.

The highly viscous polymer was discharged hot, poured onto a metalcooling plate and then ground finely in a mortar.

The determination of the glass transition temperature gave a Tg of 36.8°C.

For determination of the molecular weight distribution the solid productwas dissolved in water and the solution was filtered and subjected tomeasurement by GPC in accordance with the method specified in Example 1.The weight-average molecular weight Mw was 15 000 g/mol, thepolydispersity 5.0

Comparative Example 10, Condensation of L-lysine without Catalyst (inAnalogy to Harada, Bull. Chem. Soc. Japan 1959, 32, 1007-1008)

L-Lysine was heated at 150° C. in a Schlenk tube. After 48 hours theproduct was dissolved in water, the solution was filtered, and themolecular weight was determined as described in Example 1. Theweight-average molecular weight Mw was 2400 g/mol, the polydispersity2.2.

Comparative Example 11 in Accordance with Rohlfing et al., Arch.Biochem. Biophys. 130, 441 (1969))

L-Lysine was heated at 192° C. under a nitrogen atmosphere in a Schlenktube. After 3 hours a molecular weight Mw=7400 (polydispersity=3.9) andafter 8 hours Mw=15 900 (polydispersity=10) were found. Thereaftercrosslinking set out, and after just 24 hours 70% of the materialemployed was insoluble in water.

Comparative Example 12 in Accordance with Fox et al. (BioSystems 1976,8, 40-44, Example p. 40, top of Right-Hand Column)

L-Lysine*HCl was heated together with orthophosphoric acid (1 ml to 0.64g of lysine hydrochloride) at 195° C. in a Schlenk tube. After 10 hoursthe reaction product was dissolved in water, the acid was neutralizedwith NaOH, and the product was analyzed by GPC: weight-average molecularweight Mw=1100, polydispersity=3.1.

Comparative Example 13 in Accordance with Fox et al. (BioSystems 1976,8, 40-44)

L-Lysine*HCl was heated together with orthophosphoric acid (1 ml to 3.5g of lysine hydrochloride) at 195° C. in a Schlenk tube. After 10 hoursthe reaction product was dissolved in water, the acid was neutralizedwith NaOH, and the product was analyzed by GPC: weight-average molecularweight Mw=4300, polydispersity=1.07.

Example 14 Hydrophobic Modification of Polylysine

A 1-I four-necked flask equipped with stirrer, internal thermometer, gasinlet tube, and descending condenser with reduced-pressure connectionand receiver was charged with 100 g of L-lysine hydrochloride, 21.8 g ofsolid sodium hydroxide, and 20 g of water and the mixture was heatedwith stirring at an internal temperature of 160° C. After a reactiontime of 5 hours, water was distilled off under reduced pressure (200mbar). Then 10 g of stearic acid were added, the temperature was raisedto 180° C. and the batch was left to react for one hour under a pressureof 80 mbar with continued water separation. The highly viscous polymerwas discharged hot, poured onto a metal cooling plate and then groundfinely in a mortar.

The determination of the glass transition temperature gave a Tg of 29°C.

For determination of the molecular weight distribution the solid productwas dissolved in water and the solution was filtered and subjected tomeasurement by GPC in accordance with the method specified in Example 1.The weight-average molecular weight Mw was 7400 g/mol, thepolydispersity 3.0

Example 15 Hydrophobic Modification of Polylysine

A 1-I four-necked flask equipped with stirrer, internal thermometer, gasinlet tube, and descending condenser with reduced-pressure connectionand receiver was charged with 100 g of L-lysine hydrochloride, 21.8 g ofsolid sodium hydroxide, and 20 g of water and the mixture was heatedwith stirring at an internal temperature of 160° C. After a reactiontime of 5 hours, water was distilled off under reduced pressure (200mbar). Then 30 g of stearic acid were added, the temperature was raisedto 180° C. and the batch was left to react for one hour under a pressureof 80 mbar with continued water separation. The highly viscous polymerwas discharged hot, poured onto a metal cooling plate and then groundfinely in a mortar.

The determination of the glass transition temperature gave a Tg of 36°C.

For determination of the molecular weight distribution the solid productwas dissolved in water and the solution was filtered and subjected tomeasurement by GPC in accordance with the method specified in Example 1.The weight-average molecular weight Mw was 24100 g/mol, thepolydispersity 9.3.

Example 16 Subsequent Modification of Polylysine

7.1 g of stearic acid were added to 1.5 g of solid polylysine as perExample 9 and the mixture was heated at 150° C. in a Schlenk tube. After6 hours it was cooled to room temperature and dissolved intetrahydrofuran (THF) and the solution was filtered. Subsequently thepolymer was precipitated from acetone and the solid was isolated byfiltration and dried at 60° C. under reduced pressure.

¹H NMR (400 MHz, CDCl₃): 4.45 (mb, 1H, O═C—CH—NH—); 4.02 (m, 1H,O═C—CH—NH—) 3.19 (m, 2H, —CH₂—NH); 2.31 (t, 2H, —CH₂—CH₂—COOH); 1.61 (q,6 H, —CH₂—CH₂—COOH, CH₂—CH₂—NH); 1.26 (m, 30 H, —CH₂—CH₂—CH₂—); 0.86 (t,3 H, —CH₂—CH₃).

IR: 3280m, 3076w, 2922s, 2852m, 1637m, 1533m, 1456m, 1377w, 1246w.Example 17 Subsequent Modification of Polylysine

6.7 g of oleic acid were added to 1.5 g of solid polylysine as perExample 9 and the mixture was heated at 150° C. in a Schlenk tube. After6 hours it was cooled to room temperature and dissolved intetrahydrofuran (THF), the solution was filtered, and THF was removedunder reduced pressure on a rotary evaporator at 60° C.

¹H NMR (400 MHz, CDCl₃): 5.33 (m, 2H, —CH═CH—); 4.47 (mb, 1H,O═C—CH—NH—); 3.75 (t, 1H, O═C—CH—NH—); 3.2 (m, 2H, —CH₂—NH); 2.32 (t,2H, —CH₂—); 2.01 (d, 4 H, —CH₂—CH═CH—CH₂—); 1.85 (q, 2H,O═C—(NH)CH—CH₂—); 1.61 (m, 4 H, —CH₂—CH₂—CH₂—, CH₂—CH₂—NH); 1.28 (m, 24H, CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—NH); 0.85 (t, 3 H —CH₂—CH₃).

IR: 3295wb, 2926s, 2852m, 1709m, 1639m, 1548w, 1460w. Example 18Subsequent Modification of Polylysine

5.5 g of polyethylene glycol-carboxylic acid (average molecular weight750 g/mol) were added to 1.5 g of solid polylysine as per Example 9, andthe mixture was heated at 150° C. in a Schlenk tube. After 6 hours itwas cooled to room temperature and taken up in water, and the solutionwas filtered and freed from low molecular weight constituents using adialysis tube (MWCO 1000). Subsequently the water was removed via afreeze-drying operation.

¹H NMR (400 MHz, CDCl₃): 4.39 (m, 1H, O═C—CH—NH—); 3.92 ((m, 1H,O═C—CH—NH—); 3.7-3.2 (m, —O—CH₂—CH₂—O—); 1.91-1.04 (m, 6 H,—CH₂—CH₂—CH₂—NH, CH₂—CH₂—NH, O═C—(NH)CH—CH₂—).

IR: 3298wb, 2881s, 1657m, 1529w, 1466w, 1342m, 1279w, 1240m, 1103s,962m, 843m. Example 19 Subsequent Modification of Polylysine

7.0 g of solid polylysine as per Example 9 were suspended in 50 ml ofacetic anhydride and the mixture was boiled under reflux for 6 hours.The solvent was then removed under reduced pressure on a rotaryevaporator. The yield was quantitative.

¹H NMR (400 MHz, CDCl₃): 4.39 (m, 1H, O═C—CH—NH—); 3.92 ((m, 1H,O═C—CH—NH—); 3.25 (m, 2H, —CH₂—NH); 2.87 (m, 2H, —CH₂—NH); 1.98 (s, 3H(O)C—CH₃); 1.96 (s, 3H (O)C—CH₃); 1.75 (mb, 1 H, —CH—CH₂—CH₂—); 1.48(mb, 2H, CH₂—CH₂—NH); 1.31 (mb, 2 H, —CH₂—CH₂—CH₂—).

IR: 2931s, 2761w, 2646w, 2114w, 1635m, 1566m, 1490m, 1350m, 1304m,1241w, 1149m, 1095m, 1026s, 980m, 895m, 825w, 717m. Example 20Subsequent Modification of Polylysine

1.5 g of solid polylysine as per Example 9 were suspended in 10 ml oftrifluoroacetic anhydride and the mixture was boiled under reflux for 6hours. Then the solvent was removed under reduced pressure on a rotaryevaporator at 40° C. Subsequently the polymer was dried at roomtemperature under a high vacuum at<0.1 mbar.

Example 21 Subsequent Modification of Polylysine

1.5 g of solid polylysine as per Example 9 were suspended at 25° C. in100 ml of dry methylene chloride. After 0.3 ml of triethylamine had beenadded 6 ml of trimethylsilyl chloride were slowly added dropwise.Following the addition the mixture was stirred for 6 hours. It was thenextracted with water, the extracts were collected, and the water wasremoved under reduced pressure on a rotary evaporator at 90° C. Theyield of the modified product was quantitative.

¹H NMR (400 MHz, CDCl₃): 4.15 (mb, 1H, O═C—CH—NH—); 4.00 (m, 1H,O═C—CH—NH—); 3.88 (mb, 1H, O═C—CH—NH—); 3.16-3.07 (m, 2H, —CH₂—NH(CO));2.93 (mb, 2H, —CH₂—NH); 1.80 (mb, 1 H, —CH—CHH′—CH₂—); 1.70 (mb, 1 H,—CH—CHH′—CH₂—); 1.48 (mb, 2H, CH₂—CH₂—NH); 1.31 (mb, 2 H,—CH₂—CH₂—CH₂—); 1.18 (td, J=7.34, 3.4 Hz, 6 H, Si—(CH₃)).

IR: 3218w, 2929s, 2866w, 1660s, 1556m, 1497w, 1393w, 1252w, 1157w, 671m.Example 22 Modified Polylysine as Transport Reagent

A solution was prepared of 41.8 mg of Congo red in 1 liter of water(6*10⁻⁵ mol/l). 5 ml of this dye solution were slowly pipetted into 5 mlof a solution of 50 mg of lysine polymer from Example 16 in 5 ml ofchloroform, which was contained within a snap lid glass vessel. Twophases formed, with the dye located in the upper, aqueous phase. Thesnap lid glass was closed and shaken vigorously. After phase separation,the dye was located in the lower, chloroform phase.

The systems are depicted in FIG. 1.

Example 23 Complexing of Polylysine with Sodium Dodecyl Sulfate (SDS)

1 g of highly branched polylysine from Example 9 (8.24 mmol NH₂equivalents) was dissolved in 30 ml of MilliQ water and the pH of thesolution was adjusted to 3.5 using 0.1 M HCl. In parallel with this,2.38 g of sodium dodecyl sulfate (SDS, 8.26 mmol) were dissolved in 100ml of water and the pH of the solution was likewise adjusted to 3.5using 0.1 M HCl. The SDS solution was then added slowly, with stirring,to the aqueous solution of the polylysine, the reaction mixture turningcloudy and a precipitate being formed. After the end of the addition themixture was stirred for a further 15 minutes and the precipitate wasthen isolated by filtration. The filter residue was dissolved in 50 mlof 1-butanol and the butanolic solution was then added slowly to 500 mlof water with a pH of 3.5. The precipitate formed was again isolated byfiltration and washed copiously with 2000 ml of water adjusted to a pHof 3.5. The whitish yellow residue was dried over P₂O₅ in a desiccator.The yield was quantitative; the degree of loading of the polylysine,based on NH₂ groups, was found to be 95%.

¹H NMR (400 MHz, CD₃OD, rt): 4.28 (br, 1 H, COCH(R)NH), 4.00 (t, 2 H,J=6.92 Hz, SDS—C(1)H₂ ), 3.89 (br, 1 H, COCH(R)NH), 3.23 (m, 2 H, CH₂—NH), 2.98 (m, 2 H, CH₂ —NH₂), 1.86 (br m, 2 H, COCH(CH₂ )NH), 1.66 (q,2 H, J=6.78 Hz, SDS—C(2)H₂ ), 1.58 (br m, 2 H, CH₂ —CH₂—NH), 1.38 (br m,2 H, SDS—C(3)H₂ ), 1.35-1.20 (br m, 18 H, CH₂—CH₂ —CH₂,SDS—C(4)—SDS—(C11)H₂ ), 0.90 (d, 3 H, J=6.76 Hz, SDS—C(12)H₂ ). ¹³CNMR(100.6 MHz, CD₃OD, rt): 168.4 (COCH(R)NH), 67.36 (SDS—C(1)), 52.59(COCH(R)NH), 52.37 (COCH(R)NH), 38.45 (CH₂—NH), 38.20 (CH₂—NH), 31.14(SDS—C(2)), 30.32 (COCH(CH₂)NH), 30.12 (COCH(CH₂)NH), 28.88, 28.83,25.55, 28.52 (7×SDS—C(3)—SDS—C(9)), 29.74 (CH₂—CH₂—NH), 25.01(SDS—C(10)), 21.80 (SDS—C(11)), 21.36 (CH₂—CH₂—CH₂), 20.99(CH₂—CH₂—CH₂), 12.54 (SDS—C(12)).

Example 24 Complexing of Polylysine with Sodium Octyl Sulfate (SOS)

The procedure of Example 23 was repeated but using, instead of SDS, 1.92g of sodium octyl sulfate (SOS).

The yield of whitish yellow solid was quantitative; the degree ofloading, based on NH₂ groups, was found to be 90%.

¹H NMR (400 MHz, CD₃OD, rt): 4.29 (br, 1 H, COCH(R)NH), 4.00 (d, 2 H,J=5.46 Hz, SOS—C(1)H₂ ), 3.89 (br, 1 H, COCH(R)NH), 3.24 (m, 2 H, CH₂-NH), 2.98 (m, 2 H, CH₂ —NH2), 1.88 (br m, 2 H, COCH(CH₂ )NH), 1.67 (brm, 2 H, SOS—C(2)H₂ ), 1.60 (br m, 2 H, CH₂ —CH₂—NH), 1.40 (br m, 2 H,CH₂—CH₂ —CH₂), 1.32 (br m, 10 H, SOS—C(3)H₂ —SOS—(C7)H₂ ), 0.91 (d, 3 H,J=4.75 Hz, SOS—C(8)H₂ ).

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The systems of Example 22 are depicted in FIG. 1:

The upper phase is the water phase, the lower phase the organicchloroform phase.

Far left: water with dye—top, chloroform—bottom

2nd system from left: water with dye—top, chloroform—bottom, mixed withstearic acid (10 mg/ml), after shaking and renewed phase separation

2nd system from right: water, dye, chloroform, and stearic acid-modifiedpolylysine (10 mg/ml), after shaking and renewed phase separation

Far right: chloroform and stearic acid-modified polylysine (10 mg/ml)

1-18. (canceled)
 19. A modified polylysine comprising a polylysineobtained in any way which has been reacted with at least one furthercompound selected from the group consisting of compounds comprising acidgroups, compounds comprising isocyanate groups, compounds comprisingketo groups, compounds comprising aldehyde groups, compounds comprisingactivated double bonds, alkylene oxides, polyalkylene oxides which areterminated with amino groups or acid groups and have a functionality ofone, two or more, lactones, lactams, alkylating reagents, saturated orunsaturated long-chain carboxylic acids, amino-reactive derivatives ofsaturated or unsaturated long-chain carboxylic acids, aliphatic oraromatic isocyanates, trialkylsilyl halides, perfluoroalkyl halides, andperfluoroalkylcarboxylic acid.
 20. The modified polylysine according toclaim 19, comprising a polylysine obtained in any way which has beenmixed or reacted with at least one acidic component or salt thereof, theacidic component comprising at least one acidic group selected from thegroup consisting of carboxyl, sulfonic acid, sulfate, and phosphonicacid groups and bearing at least one substituent selected from the groupconsisting of at least one linear or branched alkyl radical, cycloalkylradicals which are optionally substituted, and aryl radicals which areoptionally substituted, which in each case can have up to 20 carbonatoms.
 21. A modified polylysine comprising a high-functionality highlybranched polylysine produced by the process of reacting (A) a salt oflysine with at least one acid, (B) optionally, at least one amino acidother than lysine, (C) optionally, at least one dicarboxylic orpolycarboxylic acid or copolymerizable derivatives thereof, and (D)optionally, at least one diamine, polyamine or copolymerizablederivatives thereof with one another in the presence of at least onecatalyst, wherein said polylysine has a weight-average molecular weightM_(w) of more than 10 000 Da and a gel content of not more than 20%,wherein said high-functionality highly branched polylysine has beenreacted with at least one further compound selected from the groupconsisting of compounds comprising acid groups, compounds comprisingisocyanate groups, compounds comprising keto groups, compoundscomprising aldehyde groups, compounds comprising activated double bonds,alkylene oxides, polyalkylene oxides which are terminated with aminogroups or acid groups and have a functionality of one, two or more,lactones, lactams, alkylating reagents, saturated or unsaturatedlong-chain carboxylic acids, amino-reactive derivatives of saturated orunsaturated long-chain carboxylic acids, aliphatic or aromaticisocyanates, trialkylsilyl halides, perfluoroalkyl halides, andperfluoroalkylcarboxylic acid.
 22. The modified polylysine according toclaim 21, comprising a polylysine obtained in any way which has beenmixed or reacted with at least one acidic component or salt thereof, theacidic component comprising at least one acidic group selected from thegroup consisting of carboxyl, sulfonic acid, sulfate, and phosphonicacid groups and bearing at least one substituent selected from the groupconsisting of at least one linear or branched alkyl radical, cycloalkylradicals which are optionally substituted, and aryl radicals which areoptionally substituted, which in each case can have up to 20 carbonatoms.
 23. A method of using a high-functionality highly branchedpolylysine produced by the process of reacting (A) a salt of lysine withat least one acid, (B) optionally, at least one amino acid other thanlysine, (C) optionally, at least one dicarboxylic or polycarboxylic acidor copolymerizable derivatives thereof, and (D) optionally, at least onediamine, polyamine or copolymerizable derivatives thereof with oneanother in the presence of at least one catalyst, wherein saidpolylysine has a weight-average molecular weight M_(w) of more than 10000 Da and a gel content of not more than 20% as an adhesion promoter orthioxotropic agent, solubilizer, phase transfer reagent forwater-insoluble chemicals, phase transfer reagent for water-solublechemicals, surface modifier or component in the production of printinginks, paints, coatings, adhesives, sealants, corrosion control products,casting elastomers or foams.
 24. A method of using a non-crosslinkedhyperbranched polylysine produced by the process of reacting (A) a saltof lysine with at least one acid, (B) optionally, at least one aminoacid other than lysine, (C) optionally, at least one dicarboxylic orpolycarboxylic acid or copolymerizable derivatives thereof, and (D)optionally, at least one diamine or polyamine or copolymerizablederivatives thereof with one another in the presence of at least onecatalyst, wherein the reaction is carried out at less than 180° C.,wherein said polylysine has a gel content of not more than 20%, as anadhesion promoter or thioxotropic agent, solubilizer, phase transferreagent for water-insoluble chemicals, phase transfer reagent forwater-soluble chemicals, surface modifier or component in the productionof printing inks, paints, coatings, adhesives, sealants, corrosioncontrol products, casting elastomers or foams.